A Common Solution to Group 2 Influenza Virus Neutralization

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Dec 17

PMID 24335589

Citations 115

Authors

Robert H E Friesen

Peter S Lee

Esther J M Stoop

Ryan M B Hoffman

Damian C Ekiert

Gira Bhabha

Wenli Yu

Jarek Juraszek

Wouter Koudstaal

Mandy Jongeneelen

Hans J W M Korse

Carla Ophorst

Els C M Brinkman-van der Linden

Mark Throsby

Mark J Kwakkenbos

Arjen Q Bakker

Tim Beaumont

Hergen Spits

Ted Kwaks

Ronald Vogels

Andrew B Ward

Jaap Goudsmit

Ian A Wilson

Affiliations

Soon will be listed here.

Abstract

The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.

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References

Wrammert J, Koutsonanos D, Li G, Edupuganti S, Sui J, Morrissey M . Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med. 2011; 208(1):181-93. PMC: 3023136. DOI: 10.1084/jem.20101352. View

Sui J, Hwang W, Perez S, Wei G, Aird D, Chen L . Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009; 16(3):265-73. PMC: 2692245. DOI: 10.1038/nsmb.1566. View

De Marco D, Clementi N, Mancini N, Solforosi L, Moreno G, Sun X . A non-VH1-69 heterosubtypic neutralizing human monoclonal antibody protects mice against H1N1 and H5N1 viruses. PLoS One. 2012; 7(4):e34415. PMC: 3319592. DOI: 10.1371/journal.pone.0034415. View

Burton D, Poignard P, Stanfield R, Wilson I . Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses. Science. 2012; 337(6091):183-6. PMC: 3600854. DOI: 10.1126/science.1225416. View

Corti D, Voss J, Gamblin S, Codoni G, Macagno A, Jarrossay D . A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science. 2011; 333(6044):850-6. DOI: 10.1126/science.1205669. View

Carrat F, Flahault A . Influenza vaccine: the challenge of antigenic drift. Vaccine. 2007; 25(39-40):6852-62. DOI: 10.1016/j.vaccine.2007.07.027. View

POTTER C . A history of influenza. J Appl Microbiol. 2001; 91(4):572-9. DOI: 10.1046/j.1365-2672.2001.01492.x. View

Stephenson I, Democratis J, Lackenby A, McNally T, Smith J, Pareek M . Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis. 2009; 48(4):389-96. DOI: 10.1086/596311. View

Schmidt A, Xu H, Khan A, ODonnell T, Khurana S, King L . Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci U S A. 2012; 110(1):264-9. PMC: 3538208. DOI: 10.1073/pnas.1218256109. View

10.

Lee P, Yoshida R, Ekiert D, Sakai N, Suzuki Y, Takada A . Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity. Proc Natl Acad Sci U S A. 2012; 109(42):17040-5. PMC: 3479480. DOI: 10.1073/pnas.1212371109. View

11.

Throsby M, van den Brink E, Jongeneelen M, Poon L, Alard P, Cornelissen L . Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One. 2008; 3(12):e3942. PMC: 2596486. DOI: 10.1371/journal.pone.0003942. View

12.

Whittle J, Zhang R, Khurana S, King L, Manischewitz J, Golding H . Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 2011; 108(34):14216-21. PMC: 3161572. DOI: 10.1073/pnas.1111497108. View

13.

Kwakkenbos M, Diehl S, Yasuda E, Bakker A, van Geelen C, Lukens M . Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med. 2009; 16(1):123-8. PMC: 2861345. DOI: 10.1038/nm.2071. View

14.

Dreyfus C, Laursen N, Kwaks T, Zuijdgeest D, Khayat R, Ekiert D . Highly conserved protective epitopes on influenza B viruses. Science. 2012; 337(6100):1343-8. PMC: 3538841. DOI: 10.1126/science.1222908. View

15.

Ekiert D, Kashyap A, Steel J, Rubrum A, Bhabha G, Khayat R . Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature. 2012; 489(7417):526-32. PMC: 3538848. DOI: 10.1038/nature11414. View

16.

Azoitei M, Correia B, Ban Y, Carrico C, Kalyuzhniy O, Chen L . Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold. Science. 2011; 334(6054):373-6. DOI: 10.1126/science.1209368. View

17.

Ekiert D, Bhabha G, Elsliger M, Friesen R, Jongeneelen M, Throsby M . Antibody recognition of a highly conserved influenza virus epitope. Science. 2009; 324(5924):246-51. PMC: 2758658. DOI: 10.1126/science.1171491. View

18.

Xu R, Krause J, McBride R, Paulson J, Crowe Jr J, Wilson I . A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin. Nat Struct Mol Biol. 2013; 20(3):363-70. PMC: 3594569. DOI: 10.1038/nsmb.2500. View

19.

Burton D . Antibodies, viruses and vaccines. Nat Rev Immunol. 2002; 2(9):706-13. DOI: 10.1038/nri891. View

20.

Azoitei M, Ban Y, Julien J, Bryson S, Schroeter A, Kalyuzhniy O . Computational design of high-affinity epitope scaffolds by backbone grafting of a linear epitope. J Mol Biol. 2011; 415(1):175-92. PMC: 7105911. DOI: 10.1016/j.jmb.2011.10.003. View